Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses

ABSTRACT

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed.

The present application is a continuation of U.S. patent applicationSer. No. 14/317,912, filed Jun. 27, 2014, which is a continuation ofU.S. patent application Ser. No. 13/417,055, filed Mar. 9, 2012, nowU.S. Pat. No. 8,802,685, which claims priority to U.S. ProvisionalPatent Application No. 61/451,806, filed Mar. 11, 2011, the entirety ofeach of which is incorporated herein by reference.

1. FIELD

Provided herein are solid forms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,pharmaceutical compositions thereof, and methods of their uses for thetreatment of diseases or disorders.

2. BACKGROUND OF THE DISCLOSURE

2.1 Pathobiology of Cancer and Other Diseases

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples include cancers of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. However, options for thetreatment of cancer are limited. For example, in the case of bloodcancers (e.g., multiple myeloma), few treatment options are available,especially when conventional chemotherapy fails and bone-marrowtransplantation is not an option. A tremendous demand therefore existsfor new methods and compositions that can be used to treat patients withcancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,TNF-α, b-FGF).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to, diabetic retinopathy, retinopathy of prematurity, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,arthritis, and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNFα, may be useful in thetreatment and prevention of various diseases and conditions.

2.2 Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein andFederman, eds., Chapter 12, Section IV). Recently, cancer therapy couldalso involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient. Additionally, surgery may not completelyremove neoplastic tissue. Radiation therapy is only effective when theneoplastic tissue exhibits a higher sensitivity to radiation than normaltissue. Radiation therapy can also often elicit serious side effects.Hormonal therapy is rarely given as a single agent. Although hormonaltherapy can be effective, it is often used to prevent or delayrecurrence of cancer after other treatments have removed the majority ofcancer cells. Biological therapies and immunotherapies are limited innumber and may produce side effects such as rashes or swellings,flu-like symptoms, including fever, chills and fatigue, digestive tractproblems or allergic reactions.

With respect to chemotherapy, there is a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove or become refractory to standard chemotherapeutictreatment protocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443.

Still, there is a significant need for safe and effective methods oftreating, preventing and managing cancer and other diseases andconditions, including for diseases that are refractory to standardtreatments, such as surgery, radiation therapy, chemotherapy andhormonal therapy, while reducing or avoiding the toxicities and/or sideeffects associated with the conventional therapies.

2.3 Solid Forms

The preparation and selection of a solid form of a pharmaceuticalcompound is complex, given that a change in solid form may affect avariety of physical and chemical properties, which may provide benefitsor drawbacks in processing, formulation, stability and bioavailability,among other important pharmaceutical characteristics. Potentialpharmaceutical solids include crystalline solids and amorphous solids.Amorphous solids are characterized by a lack of long-range structuralorder, whereas crystalline solids are characterized by structuralperiodicity. The desired class of pharmaceutical solid depends upon thespecific application; amorphous solids are sometimes selected on thebasis of, e.g., an enhanced dissolution profile, while crystallinesolids may be desirable for properties such as, e.g., physical orchemical stability (see, e.g., S. R. Vippagunta et al., Adv. Drug.Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001)48:27-42).

Whether crystalline or amorphous, potential solid forms of apharmaceutical compound include single-component and multiple-componentsolids. Single-component solids consist essentially of thepharmaceutical compound in the absence of other compounds. Variety amongsingle-component crystalline materials may potentially arise, e.g., fromthe phenomenon of polymorphism, wherein multiple three-dimensionalarrangements exist for a particular pharmaceutical compound (see, e.g.,S. R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, WestLafayette). The importance of studying polymorphs was underscored by thecase of Ritonavir, an HIV protease inhibitor that was formulated as softgelatin capsules. About two years after the product was launched, theunanticipated precipitation of a new, less soluble polymorph in theformulation necessitated the withdrawal of the product from the marketuntil a more consistent formulation could be developed (see S. R.Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417).

Additional diversity among the potential solid forms of a pharmaceuticalcompound may arise, e.g., from the possibility of multiple-componentsolids. Crystalline solids comprising two or more ionic species may betermed salts (see, e.g., Handbook of Pharmaceutical Salts: Properties,Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley,Weinheim). Additional types of multiple-component solids that maypotentially offer other property improvements for a pharmaceuticalcompound or salt thereof include, e.g., hydrates, solvates, co-crystalsand clathrates, among others (see, e.g., S. R. Byrn et al., Solid StateChemistry of Drugs, (1999) SSCI, West Lafayette). Moreover,multiple-component crystal forms may potentially be susceptible topolymorphism, wherein a given multiple-component composition may existin more than one three-dimensional crystalline arrangement. Thepreparation of solid forms is of great importance in the development ofa safe, effective, stable and marketable pharmaceutical compound.

Provided herein are embodiments addressing a need for solid forms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione(“Compound A”). Compound A was described in U.S. Pat. No. 7,635,700, thedisclosure of which is incorporated herein by reference in its entirety.

3. SUMMARY

This disclosure relates to methods of treating diseases and disordersutilizing a solid form of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or astereoisomer thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof.

Provided herein are solid forms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or astereoisomer thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof. In one embodiment,the solid form is crystalline Form A. In another embodiment, the solidform is crystalline Form B. In yet another embodiment, the solid form iscrystalline Form C. In yet another embodiment, the solid form is Form D.In yet another embodiment, the solid form is crystalline Form E. In yetanother embodiment, the solid form is crystalline Form F. In yet anotherembodiment, the solid form is a solid form of a hydrochloride salt of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Instill another embodiment, the solid form is crystalline Form A1.

Further provided herein are pharmaceutical compositions, single unitdosage forms, dosing regimens, and kits, which comprise a solid form of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or astereoisomer thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof; and apharmaceutically acceptable carrier.

Additionally provided herein are methods of treating and managingvarious diseases or disorders, which comprise administering to a patienta therapeutically effective amount of a solid form of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or astereoisomer thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof.

Also provided herein are methods of preventing various diseases anddisorders, which comprise administering to a patient a prophylacticallyeffective amount of a solid form of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or astereoisomer thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof.

In certain embodiments, the solid forms are single-component crystalforms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Incertain embodiments, the solid forms are multiple-component crystalforms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,including, but not limited to, salts, co-crystals and/or solvates(including hydrates) comprising3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Incertain embodiments, the solid forms are single-component amorphousforms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Incertain embodiments, the solid forms are multiple-component amorphousforms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.Without intending to be limited by any particular theory, certain solidforms provided herein have particular advantageous physical and/orchemical properties making them useful, e.g., for manufacturing,processing, formulation and/or storage, while also possessingparticularly advantageous biological properties, such as, e.g.,bioavailability and/or biological activity.

In certain embodiments, solid forms provided herein include solid formscomprising3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,including, but not limited to, single-component and multiple-componentsolid forms comprising3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Incertain embodiments, solid forms provided herein include salts,polymorphs, solvates (including hydrates), and co-crystals comprising3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.Certain embodiments herein provide methods of making, isolating and/orcharacterizing the solid forms provided herein.

The solid forms provided herein are useful as active pharmaceuticalingredients for the preparation of formulations for use in patients.Thus, embodiments herein encompass the use of these solid forms as afinal drug product. Certain embodiments provide solid forms useful inmaking final dosage forms with improved properties, e.g., powder flowproperties, compaction properties, tableting properties, stabilityproperties, and excipient compatibility properties, among others, thatare needed for manufacturing, processing, formulation and/or storage offinal drug products. Certain embodiments herein provide pharmaceuticalcompositions comprising a single-component crystal form, amultiple-component crystal form, a single-component amorphous formand/or a multiple-component amorphous form comprising3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione and apharmaceutically acceptable diluent, excipient or carrier. The solidforms and the final drug products provided herein are useful, forexample, for the treatment, prevention or management of diseases anddisorders provided herein.

3.1. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides an X-ray Powder Diffraction (“XRPD”) pattern of Form Aof 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 2 provides a Differential Scanning Calorimetry (“DSC”) plot of FormA of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 3 provides a Thermal Gravimetric Analysis (“TGA”) plot of Form A of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 4 provides an XRPD pattern of Form B of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 5 provides a DSC plot of Form B of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 6 provides a TGA plot of Form B of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 7 provides an XRPD pattern of Form C of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 8 provides a DSC plot of Form C of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 9 provides a TGA plot of Form C of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 10 provides an XRPD pattern of Form D of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 11 provides a DSC plot of Form D of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 12 provides a TGA plot of Form D of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 13 provides an XRPD pattern of Form E of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 14 provides a DSC plot of Form E of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 15 provides a TGA plot of Form E of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 16 provides an XRPD pattern of Form F of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 17 provides a DSC plot of Form F of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 18 provides an XRPD pattern of Form A1 of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrochloride.

FIG. 19 provides a DSC plot of Form A1 of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrochloride.

FIG. 20 provides a TGA plot of Form A1 of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrochloride.

FIG. 21 provides a Dynamic Vapor Sorption (“DVS”) plot of Form A1 of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrochloride.

FIG. 22 is a microscopic image of crystals of Form A1 of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrochloride.

FIG. 23 depicts interconversions between various solid forms of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 24 depicts the solubility of Form A of Compound A in DMSO:water.

3.2. DEFINITIONS

As used herein, term “Compound A” refers to3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. The¹H NMR spectrum of Compound A is substantially as follows: δ (DMSO-d₆):2.10-2.17 (m, 1H), 2.53 (s, 3H), 2.59-2.69 (m, 2H), 2.76-2.89 (m, 1H),5.14 (dd, J=6, 11 Hz, 1H), 6.56 (d, J=8 Hz, 1H), 6.59 (d, J=8 Hz, 1H),7.02 (s, 2H), 7.36 (t, J=8 Hz, 1H), 10.98 (s, 1H). The ¹³C NMR spectrumof Compound A is substantially as follows: δ (DMSO-d₆): 20.98, 23.14,30.52, 55.92, 104.15, 110.48, 111.37, 134.92, 148.17, 150.55, 153.62,162.59, 169.65, 172.57.

Without being limited by theory, Compound A is believed to be3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,which has the following structure:

As used herein, the term “patient” refers to a mammal, particularly ahuman.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from a pharmaceutically acceptable non-toxic acid or base,including inorganic acids and bases and organic acids and bases.

As used herein, term “adverse effects” includes, but is not limited togastrointestinal, renal and hepatic toxicities, leukopenia, increases inbleeding times due to, e.g., thrombocytopenia, and prolongation ofgestation, nausea, vomiting, somnolence, asthenia, dizziness,teratogenicity, extra-pyramidal symptoms, akathisia, cardiotoxicityincluding cardiovascular disturbances, inflammation, male sexualdysfunction, and elevated serum liver enzyme levels. The term“gastrointestinal toxicities” includes, but is not limited to, gastricand intestinal ulcerations and erosions. The term “renal toxicities”includes, but is not limited to, such conditions as papillary necrosisand chronic interstitial nephritis.

As used herein and unless otherwise indicated, the phrases “reduce oravoid adverse effects” and “reducing or avoiding adverse effects” meanthe reduction of the severity of one or more adverse effects as definedherein.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

As used herein and unless otherwise specified, the terms “solid form”and related terms refer to a physical form which is not predominantly ina liquid or a gaseous state. As used herein and unless otherwisespecified, the term “solid form” and related terms, when used herein torefer to Compound A, refer to a physical form comprising Compound Awhich is not predominantly in a liquid or a gaseous state. Solid formsmay be crystalline, amorphous, or mixtures thereof. In particularembodiments, solid forms may be liquid crystals. A “single-component”solid form comprising Compound A consists essentially of Compound A. A“multiple-component” solid form comprising Compound A comprises asignificant quantity of one or more additional species, such as ionsand/or molecules, within the solid form. In certain embodiments, a“multiple-component” solid form comprising Compound A comprises ahydrochloride salt of compound A. For example, in particularembodiments, a crystalline multiple-component solid form comprisingCompound A further comprises one or more species non-covalently bondedat regular positions in the crystal lattice. Multiple-component solidforms comprising Compound A include co-crystals, solvates (e.g.,hydrates), and clathrates of Compound A. In particular embodiments, theterm “solid form comprising Compound A” and related terms includesingle-component and multiple-component solid forms comprising CompoundA. In particular embodiments, “solid forms comprising Compound A” andrelated terms include crystal forms comprising Compound A, amorphousforms comprising Compound A, and mixtures thereof.

As used herein and unless otherwise specified, the term “crystalline”and related terms used herein, when used to describe a compound,substance, modification, material, component or product, unlessotherwise specified, mean that the compound, substance, modification,material, component or product is substantially crystalline asdetermined by X-ray diffraction. See, e.g., Remington: The Science andPractice of Pharmacy, 21^(st) edition, Lippincott, Williams and Wilkins,Baltimore, Md. (2005); The United States Pharmacopeia, 23^(rd) ed.,1843-1844 (1995).

As used herein and unless otherwise specified, the term “crystal forms,”“crystalline forms” and related terms herein refer to solid forms thatare crystalline. Crystal forms include single-component crystal formsand multiple-component crystal forms, and include, but are not limitedto, salts (e.g., a hydrochloride salt), polymorphs, solvates, hydrates,and/or other molecular complexes. In certain embodiments, a crystal formof a substance may be substantially free of amorphous forms and/or othercrystal forms. In certain embodiments, a crystal form of a substance maycontain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more amorphous formsand/or other crystal forms on a weight basis. In certain embodiments, acrystal form of a substance may be physically and/or chemically pure. Incertain embodiments, a crystal form of a substance may be about 99%,98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/orchemically pure.

As used herein and unless otherwise specified, the terms “polymorphs,”“polymorphic forms” and related terms herein, refer to two or morecrystal forms that consist essentially of the same molecule, molecules,and/or ions. Like different crystal forms, different polymorphs may havedifferent physical properties such as, e.g., melting temperature, heatof fusion, solubility, dissolution properties and/or vibrationalspectra, as a result of the arrangement or conformation of the moleculesand/or ions in the crystal lattice. The differences in physicalproperties may affect pharmaceutical parameters such as storagestability, compressibility and density (important in formulation andproduct manufacturing), and dissolution rate (an important factor inbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical changes (e.g., tabletscrumble on storage as a kinetically favored polymorph converts tothermodynamically more stable polymorph) or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somesolid-state transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties may be importantin processing (e.g., one polymorph might be more likely to form solvatesor might be difficult to filter and wash free of impurities, andparticle shape and size distribution might be different betweenpolymorphs).

As used herein and unless otherwise specified, the terms “solvate” and“solvated,” refer to a crystal form of a substance which containssolvent. The terms “hydrate” and “hydrated” refer to a solvate whereinthe solvent comprises water. “Polymorphs of solvates” refers to theexistence of more than one crystal form for a particular solvatecomposition. Similarly, “polymorphs of hydrates” refers to the existenceof more than one crystal form for a particular hydrate composition. Theterm “desolvated solvate,” as used herein, refers to a crystal form of asubstance which may be prepared by removing the solvent from a solvate.

As used herein and unless otherwise specified, the term “amorphous,”“amorphous form,” and related terms used herein, mean that thesubstance, component or product in question is not substantiallycrystalline as determined by X-ray diffraction. In particular, the term“amorphous form” describes a disordered solid form, i.e., a solid formlacking long range crystalline order. In certain embodiments, anamorphous form of a substance may be substantially free of otheramorphous forms and/or crystal forms. In other embodiments, an amorphousform of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other amorphousforms and/or crystal forms on a weight basis. In certain embodiments, anamorphous form of a substance may be physically and/or chemically pure.In certain embodiments, an amorphous form of a substance be about 99%,98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/orchemically pure.

Techniques for characterizing crystal forms and amorphous forms include,but are not limited to, thermal gravimetric analysis (TGA), differentialscanning calorimetry (DSC), X-ray powder diffractometry (XRPD),single-crystal X-ray diffractometry, vibrational spectroscopy, e.g.,infrared (IR) and Raman spectroscopy, solid-state and solution nuclearmagnetic resonance (NMR) spectroscopy, optical microscopy, hot stageoptical microscopy, scanning electron microscopy (SEM), electroncrystallography and quantitative analysis, particle size analysis (PSA),surface area analysis, solubility measurements, dissolutionmeasurements, elemental analysis, and Karl Fischer analysis.Characteristic unit cell parameters may be determined using one or moretechniques such as, but not limited to, X-ray diffraction and neutrondiffraction, including single-crystal diffraction and powderdiffraction. Techniques useful for analyzing powder diffraction datainclude profile refinement, such as Rietveld refinement, which may beused, e.g., to analyze diffraction peaks associated with a single phasein a sample comprising more than one solid phase. Other methods usefulfor analyzing powder diffraction data include unit cell indexing, whichallows one of skill in the art to determine unit cell parameters from asample comprising crystalline powder.

As used herein and unless otherwise specified, the terms “about” and“approximately,” when used in connection with a numeric value or a rangeof values which is provided to characterize a particular solid form,e.g., a specific temperature or temperature range, such as, e.g., thatdescribing a DSC or TGA thermal event, including, e.g., melting,dehydration, desolvation or glass transition events; a mass change, suchas, e.g., a mass change as a function of temperature or humidity; asolvent or water content, in terms of, e.g., mass or a percentage; or apeak position, such as, e.g., in analysis by IR or Raman spectroscopy orXRPD; indicate that the value or range of values may deviate to anextent deemed reasonable to one of ordinary skill in the art while stilldescribing the particular solid form. For example, in particularembodiments, the terms “about” and “approximately,” when used in thiscontext and unless otherwise specified, indicate that the numeric valueor range of values may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%,5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or rangeof values.

As used herein and unless otherwise specified, a sample comprising aparticular crystal form or amorphous form that is “substantially pure,”e.g., substantially free of other solid forms and/or of other chemicalcompounds, contains, in particular embodiments, less than about 25%,20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or0.1% percent by weight of one or more other solid forms and/or of otherchemical compounds.

As used herein and unless otherwise specified, a sample or compositionthat is “substantially free” of one or more other solid forms and/orother chemical compounds means that the composition contains, inparticular embodiments, less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% percent by weight ofone or more other solid forms and/or other chemical compounds.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a patient with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of diseases or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a patientderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients (and in the specified amounts, ifindicated), as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. By “pharmaceutically acceptable” it is meant that thediluent, excipient or carrier must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

4. DETAILED DESCRIPTION

This disclosure relates to solid forms of Compound A, which is3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, andstereoisomers thereof, and pharmaceutically acceptable salts, solvates,hydrates, co-crystals, clathrates, and polymorphs thereof; as well asmethods of using, and compositions comprising, a solid form of CompoundA or a stereoisomer thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Forexample, the present disclosure encompasses the in vitro and in vivo useof a solid form of Compound A, and the incorporation of a solid form ofCompound A into pharmaceutical compositions and single unit dosage formsuseful in the treatment and prevention of a variety of diseases anddisorders.

4.1. Solid Forms of Compound A

In one embodiment, provided herein are solid forms of Compound A or astereoisomer thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof.

Compound A is readily prepared using the methods as described in U.S.Pat. No. 7,635,700, the disclosure of which is incorporated herein byreference in its entirety.

Solid forms comprising Compound A include single-component andmultiple-component forms, including crystal forms and amorphous forms,and including, but not limited to, salts, polymorphs, solvates,hydrates, co-crystals and clathrates. Particular embodiments hereinprovide single-component amorphous solid forms of Compound A. Particularembodiments herein provide single-component crystalline solid forms ofCompound A. Particular embodiments herein provide multiple-componentamorphous forms comprising Compound A. Particular embodiments hereinprovide multiple-component crystalline solid forms comprising CompoundA. Multiple-component solid forms provided herein include solid formswhich may be described by the terms salt, co-crystal, hydrate, solvate,clathrate and/or polymorph, and include solid forms which may bedescribed by one or more of these terms.

Solid forms comprising Compound A can be prepared by the methodsdescribed herein, including the methods described in the Examples below,or by techniques known in the art, including heating, cooling, freezedrying, lyophilization, quench cooling the melt, rapid solventevaporation, slow solvent evaporation, solvent recrystallization,antisolvent addition, slurry recrystallization, crystallization from themelt, desolvation, recrystallization in confined spaces such as, e.g.,in nanopores or capillaries, recrystallization on surfaces or templatessuch as, e.g., on polymers, recrystallization in the presence ofadditives, such as, e.g., co-crystal counter-molecules, desolvation,dehydration, rapid cooling, slow cooling, exposure to solvent and/orwater, drying, including, e.g., vacuum drying, vapor diffusion,sublimation, grinding (including, e.g., cryo-grinding, solvent-dropgrinding or liquid assisted grinding), microwave-induced precipitation,sonication-induced precipitation, laser-induced precipitation andprecipitation from a supercritical fluid. The particle size of theresulting solid forms, which can vary, (e.g., from nanometer dimensionsto millimeter dimensions), can be controlled, e.g., by varyingcrystallization conditions, such as, e.g., the rate of crystallizationand/or the crystallization solvent system, or by particle-size reductiontechniques, e.g., grinding, milling, micronizing or sonication.

While not intending to be bound by any particular theory, certain solidforms are characterized by physical properties, e.g., stability,solubility and dissolution rate, appropriate for pharmaceutical andtherapeutic dosage forms. Moreover, while not wishing to be bound by anyparticular theory, certain solid forms are characterized by physicalproperties (e.g., density, compressibility, hardness, morphology,cleavage, stickiness, solubility, water uptake, electrical properties,thermal behavior, solid-state reactivity, physical stability, andchemical stability) affecting particular processes (e.g., yield,filtration, washing, drying, milling, mixing, tableting, flowability,dissolution, formulation, and lyophilization) which make certain solidforms suitable for the manufacture of a solid dosage form. Suchproperties can be determined using particular analytical chemicaltechniques, including solid-state analytical techniques (e.g., X-raydiffraction, microscopy, spectroscopy and thermal analysis), asdescribed herein and known in the art.

Certain embodiments herein provide compositions comprising one or moreof the solid forms. Certain embodiments provide compositions of one ormore solid forms in combination with other active ingredients. Certainembodiments provide methods of using these compositions in thetreatment, prevention or management of diseases and disorders including,but not limited to, the diseases and disorders provided herein.

Solid forms provided herein may also comprise unnatural proportions ofatomic isotopes at one or more of the atoms in Compound A. For example,the compound may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I) sulfur-35 (³⁵S), or carbon-14(¹⁴C). Radiolabeled compounds are useful as therapeutic agents, e.g.,cancer therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of Compound A, whether radioactive or not, areintended to be encompassed within the scope of the embodiments providedherein.

4.1.1. Form A of Compound A

Certain embodiments herein provide crystalline Form A of Compound A.Form A may be crystallized from DMSO:water at room temperature,dissolving Compound A in 95:5 DMSO:water (v:v) and crystallizing byadding water to reach 50:50 DMSO:water (v:v). A wide screen of solventsresulted in the selection of DMSO:water, with water being theanti-solvent. Table 1 (FIG. 24) shows the solubility of Form A inDMSO:water as the relative amount of DMSO is increased.

In certain embodiments, Form A of Compound A may be characterized byX-ray powder diffraction analysis. A representative XRPD pattern of FormA of Compound A is provided in FIG. 1. In certain embodiments, Form A ofCompound A is characterized by XRPD peaks located at one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen ofthe following approximate positions: 9.2, 13.4, 14.0, 14.6, 15.6, 16.7,18.5, 21.9, 22.7, 24.8, 28.1, 30.0 and 37.0 degrees 2θ. In oneembodiment, the Form A of Compound A is characterized by XRPD peakslocated at the following approximate positions: 14.6, 15.6, 16.7, 21.9and 30.0, degrees 2θ. In certain embodiments, Form A of Compound A ischaracterized by an XRPD pattern which matches the pattern exhibited inFIG. 1. In certain embodiments, Form A of Compound A is characterized byan XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 peaksmatching peaks in the representative Form A pattern provided herein.

In certain embodiments, Form A of Compound A may be characterized bythermal analysis. A representative DSC plot for Form A of Compound A isshown in FIG. 2. In certain embodiments, Form A is characterized by aDSC plot comprising an endothermic event with an onset temperature ofabout 282° C. In certain embodiments, a characteristic Form A DSC plotfurther comprises one or more additional events, such as, e.g., anendothermic event with a peak temperature of about 145° C., and/or anexothermic event with a peak temperature of about 161° C. Arepresentative TGA plot for Form A of Compound A is shown in FIG. 3. Incertain embodiments, Form A is characterized by a TGA plot comprising amass loss of less than about 10%, less than about 8%, or less than about6%, e.g., about 5.9%, of the total mass of the sample upon heating fromabout 40° C. to about 110° C. In one embodiment, Form A is characterizedby a TGA plot comprising a mass loss of about 5 to about 6% of the totalmass of the sample upon heating from about 40° C. to about 110° C. Incertain embodiments, Form A of Compound A contains either water or othersolvent in the crystal lattice. In certain embodiments, the TGA massloss event comprises the loss of water. In certain embodiments, Form Ais solvated. In certain embodiments, Form A is monohydrated. In certainembodiments, the crystal lattice of Form A comprises about one molarequivalent of water per mole of Compound A.

In certain embodiments, upon dehydration Form A is converted to Form Dof Compound A. In one embodiment, Form A is converted to Form D ofCompound A when dried at about 55° C. for 3 days. Form A of Compound Amay be prepared from Form D by slurrying Form D in water at 22° C. or50° C. overnight.

In one embodiment, Form A of Compound A is physically and chemicallystable at 40° C. for 5 days under vacuum. In another embodiment, Form Aof Compound A is physically and chemically stable at 40° C. for 4 daysunder nitrogen atmosphere.

In certain embodiments, Form A of Compound A may be characterized bymoisture sorption analysis. In certain embodiments, when the relativehumidity (“RH”) is increased from about 0% to about 95% RH, Form Aexhibits a mass change ranging from about 1% to about 10%, from about 2to about 5%, or from about 3 to about 4% of the starting mass of thesample. In certain embodiments, mass gained upon adsorption is lost whenthe RH is decreased back to about 0% RH.

Certain embodiments herein provide Form A of Compound A which issubstantially pure. Certain embodiments herein provide Form A ofCompound A which is substantially free of other solid forms comprisingCompound A including, e.g., Forms B, C, D, E, and F and/or an amorphoussolid form comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein. Certain embodiments herein provide Form A as a mixture of solidforms comprising Compound A, including, e.g., a mixture comprising oneor more of the following: Forms B, C, D, E, F, and an amorphous solidform comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein.

4.1.2. Form B of Compound A

Certain embodiments herein provide crystalline Form B of Compound A. Incertain embodiments, Form B of Compound A can be obtained from varioussolvents, including, but not limited to, solvent systems comprisingacetone, acetonitrile, methanol, and mixtures thereof. In certainembodiments, Form B can be obtained using a slurry recrystallizationprocess. In certain embodiments, Form B is obtained using a slurryrecrystallization process in acetone, acetonitrile, methanol, ormixtures thereof at about 50° C.

In certain embodiments, Form B of Compound A may be characterized byX-ray powder diffraction analysis. A representative XRPD pattern of FormB of Compound A is provided in FIG. 4. In certain embodiments, Form B ofCompound A is characterized by XRPD peaks located at one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen or sixteen of the following approximate positions:10.6, 11.4, 12.6, 13.7, 14.7, 19.1, 20.3, 20.9, 21.2, 22.9, 24.9, 25.3,25.9, 26.9, 29.5 and 33.8 degrees 2θ. In one embodiment, Form B ofCompound A is characterized by XRPD peaks located at the followingapproximate positions: 10.6, 14.7, 19.1 and 25.9 degrees 2θ. In certainembodiments, Form B of Compound A is characterized by an XRPD patternwhich matches the pattern exhibited in FIG. 4. In certain embodiments,Form B of Compound A is characterized by an XRPD pattern having 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 peaks matching peaks inthe representative Form B pattern provided herein.

In certain embodiments, Form B of Compound A may be characterized bythermal analysis. A representative DSC plot for Form B of Compound A isshown in FIG. 5. In certain embodiments, Form B is characterized by aDSC plot comprising an endothermic event with an onset temperature ofabout 279° C. A representative TGA plot for Form B of Compound A isshown in FIG. 6. In certain embodiments, Form B is characterized by aTGA plot comprising a mass loss of less than about 1%, less than about0.5%, less than about 0.1%, or less than 0.05% of the total mass of thesample upon heating from about 25° C. to about 200° C. In certainembodiments, Form B of Compound A does not contain substantial amountsof either water or other solvent in the crystal lattice. In certainembodiments, Form B is anhydrous. In certain embodiments, Form B isunsolvated.

In certain embodiments, Form B of Compound A may be characterized bymoisture sorption analysis. In certain embodiments, when the RH isincreased from about 0% to about 95% RH, Form B exhibits a mass changeof less than about 1%, less than about 0.5%, or less than about 0.2%,e.g., about 0.1%, of the starting mass of the sample. In certainembodiments, mass gained upon adsorption is lost when the RH isdecreased back to about 0% RH. In certain embodiments, Form B issubstantially nonhygroscopic. In certain embodiments, the XRPD patternof Form B material is substantially unchanged following theadsorption/desorption analysis. In certain embodiments, Form B is stablewith respect to humidity.

Certain embodiments herein provide Form B of Compound A which issubstantially pure. Certain embodiments herein provide Form B ofCompound A which is substantially free of other solid forms comprisingCompound A including, e.g., Forms A, C, D, E, F, and/or an amorphoussolid form comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein. Certain embodiments herein provide Form B as a mixture of solidforms comprising Compound A, including, e.g., a mixture comprising oneor more of the following: Forms A, C, D, E, F, and an amorphous solidform comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein.

4.1.3. Form C of Compound A

Certain embodiments herein provide crystalline Form C of Compound A. Incertain embodiments, Form C of Compound A can be obtained from varioussolvents, including, but not limited to, solvent systems comprisingethyl acetate, ethanol, 2-propanol, methyl ethyl ketone, n-butanol,tetrahydrofuran, and mixtures comprising two or more thereof. In certainembodiments, Form C can be obtained using a slurry recrystallizationprocess. In certain embodiments, Form C is obtained using a slurryrecrystallization process in ethyl acetate, ethanol, 2-propanol, methylethyl ketone, n-butanol, tetrahydrofuran, or mixtures comprising two ormore thereof, at about 50° C.

In certain embodiments, Form C of Compound A may be characterized byX-ray powder diffraction analysis. A representative XRPD pattern of FormC of Compound A is provided in FIG. 7. In certain embodiments, Form C ofCompound A is characterized by XRPD peaks located at one, two, three,four, five, six, seven, eight, nine, ten or eleven of the followingapproximate positions: 10.8, 11.9, 15.1, 18.8, 19.2, 19.3, 22.0, 24.9,25.1, 26.6 and 29.2 degrees 2θ. In one embodiment, Form C of Compound Ais characterized by XRPD peaks located at the following approximatepositions: 10.8, 15.1, 25.1 and 26.6 degrees 2θ. In certain embodiments,Form C of Compound A is characterized by an XRPD pattern which matchesthe pattern exhibited in FIG. 7. In certain embodiments, Form C ofCompound A is characterized by an XRPD pattern having 1, 2, 3, 4, 5, 6,7, 8, 9, 10 or 11 peaks matching peaks in the representative Form Cpattern provided herein.

In certain embodiments, Form C of Compound A may be characterized bythermal analysis. A representative DSC plot for Form C of Compound A isshown in FIG. 8. In certain embodiments, Form C is characterized by aDSC plot comprising an endothermic event with an onset temperature ofabout 281° C. A representative TGA plot for Form C of Compound A isshown in FIG. 9. In certain embodiments, Form C is characterized by aTGA plot comprising a mass loss of less than about 1%, less than about0.5%, or less than about 0.1%, e.g., about 0.07%, of the total mass ofthe sample upon heating from about 25° C. to about 150° C. In certainembodiments, Form C of Compound A does not contain substantial amountsof either water or other solvent in the crystal lattice. In certainembodiments, Form C is anhydrous. In certain embodiments, Form C isunsolvated.

In certain embodiments, Form C of Compound A may be characterized bymoisture sorption analysis. In certain embodiments, when the RH isincreased from about 0% to about 95% RH, Form C exhibits a mass changeof less than about 1%, less than about 0.5%, or less than about 0.2%,e.g., about 0.17%, of the starting mass of the sample. In certainembodiments, mass gained upon adsorption is lost when the RH isdecreased back to about 0% RH. In certain embodiments, Form C issubstantially nonhygroscopic. In certain embodiments, the XRPD patternof Form C material is substantially unchanged following theadsorption/desorption analysis. In certain embodiments, Form C is stablewith respect to humidity.

Certain embodiments herein provide Form C of Compound A which issubstantially pure. Certain embodiments herein provide Form C ofCompound A which is substantially free of other solid forms comprisingCompound A including, e.g., Forms A, B, D, E, F, and/or an amorphoussolid form comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein. Certain embodiments herein provide Form C as a mixture of solidforms comprising Compound A, including, e.g., a mixture comprising oneor more of the following: Forms A, B, D, E, F, and an amorphous solidform comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein.

4.1.4. Form D of Compound A

Certain embodiments herein provide Form D of Compound A. In certainembodiments, Form D of Compound A can be obtained by drying Form A ofCompound A in an oven. In certain embodiments, Form D is obtained bydrying Form A in an oven at about 70° C.

In certain embodiments, Form D of Compound A may be characterized byX-ray powder diffraction analysis. A representative XRPD pattern of FormD of Compound A is provided in FIG. 10. In certain embodiments, Form Dof Compound A is characterized by an XRPD pattern which matches thepattern exhibited in FIG. 10. In certain embodiments, Form D of CompoundA is characterized by XRPD peaks located at one, two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen ofthe following approximate positions: 10.6, 14.0, 14.6, 15.7, 16.3, 16.7,18.8, 21.7, 21.9, 24.8, 25.1, 25.8, 28.1 and 28.6 degrees 2θ. In oneembodiment, Form D of Compound A is characterized by XRPD peaks locatedat the following approximate positions: 16.7, 21.7, 21.9 and 25.8degrees 2θ. In certain embodiments, Form D of Compound A ischaracterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 peaks matching peaks in the representative Form Dpattern provided herein.

In certain embodiments, Form D of Compound A may be characterized bythermal analysis. A representative DSC plot for Form D of Compound A isshown in FIG. 11. In certain embodiments, Form D is characterized by aDSC plot comprising an endothermic event with an onset temperature ofabout 283° C. In certain embodiments, a characteristic Form D DSC plotfurther comprises one additional event, such as, e.g., an endothermicevent with a peak temperature of about 114° C. A representative TGA plotfor Form D of Compound A is shown in FIG. 12. In certain embodiments,Form D is characterized by a TGA plot comprising a mass loss of lessthan about 10%, less than about 8%, less than about 6%, less than about4%, e.g., about 3%, of the total mass of the sample upon heating fromabout 25° C. to about 150° C. In certain embodiments, the TGA mass lossevent comprises the loss of water. In certain embodiments, Form D ofCompound A is solvated. In certain embodiments, Form D is hydrated.

In certain embodiments, Form D of Compound A may be characterized bymoisture sorption analysis. In certain embodiments, when the RH isincreased from about 0% to about 95% RH, Form D exhibits a mass changeof less than about 5%, e.g., about 4%, of the starting mass of thesample. In certain embodiments, mass gained upon adsorption is lost whenthe RH is decreased back to about 0% RH.

Certain embodiments herein provide Form D of Compound A which issubstantially pure. Certain embodiments herein provide Form D ofCompound A which is substantially free of other solid forms comprisingCompound A including, e.g., Forms A, B, C, D, E, F, and/or an amorphoussolid form comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein. Certain embodiments herein provide Form D as a mixture of solidforms comprising Compound A, including, e.g., a mixture comprising oneor more of the following: Forms A, B, C, E, F, and an amorphous solidform comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein.

4.1.5. Form E of Compound A

Certain embodiments herein provide the Form E crystal form of CompoundA. In certain embodiments, Form E of Compound A can be obtained fromvarious solvents, including, but not limited to, solvent systemscomprising acetonitrile or isopropanol, and mixtures thereof. In certainembodiments, Form E can be obtained using a slurry recrystallizationprocess. In certain embodiments, Form E can be obtained using a slurryrecrystallization process at room temperature. Form E can also beobtained by an antisolvent recrystallization process by dissolvingCompound A in DMF or NMP and rapidly adding water as antisolvent.

In certain embodiments, Form E of Compound A may be characterized byX-ray powder diffraction analysis. A representative XRPD pattern of FormE of Compound A is provided in FIG. 13. In certain embodiments, Form Eof Compound A is characterized by XRPD peaks located at one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve or thirteen ofthe following approximate positions: 7.3, 9.3, 12.2, 14.0, 14.6, 15.7,16.8, 21.0, 22.0, 22.7, 29.4, 30.0 and 37.0 degrees 2θ. In oneembodiment, Form E of Compound A is characterized by XRPD peaks locatedat the following approximate positions: 7.3, 14.6, 22.0, 30.0 and 37.0degrees 2θ. In certain embodiments, Form E of Compound A ischaracterized by an XRPD pattern which matches the pattern exhibited inFIG. 13. In certain embodiments, Form E of Compound A is characterizedby an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13peaks matching peaks in the representative Form E pattern providedherein.

In certain embodiments, Form E of Compound A may be characterized bythermal analysis. A representative DSC plot for Form E of Compound A isshown in FIG. 14. In certain embodiments, Form E is characterized by aDSC plot comprising an endothermic event with an onset temperature ofabout 279° C. In certain embodiments, a characteristic Form E DSC plotfurther comprises one additional event, such as, e.g., an endothermicevent with a peak temperature of about 146° C. A representative TGA plotfor Form E of Compound A is shown in FIG. 15. In certain embodiments,Form E is characterized by a TGA plot comprising a mass loss of lessthan about 10%, less than about 8%, less than about 6%, e.g., about5.97%, of the total mass of the sample upon heating from about 25° C. toabout 150° C. In certain embodiments, the TGA mass loss event comprisesthe loss of water. In certain embodiments, Form E of Compound A issolvated. In certain embodiments, Form E is hydrated.

In certain embodiments, Form E of Compound A may be characterized bymoisture sorption analysis. In certain embodiments, when the RH isincreased from about 0% to about 95% RH, Form E exhibits a mass changeof less than about 2%, less than about 1%, or less than about 0.5%,e.g., about 0.4%, of the starting mass of the sample. In certainembodiments, mass gained upon adsorption is lost when the RH isdecreased back to about 0% RH. In certain embodiments, Form E isnonhygroscopic. In certain embodiments, the XRPD pattern of Form Ematerial is substantially unchanged following the adsorption/desorptionanalysis. In certain embodiments, Form E is stable with respect tohumidity.

Certain embodiments herein provide Form E of Compound A which issubstantially pure. Certain embodiments herein provide Form E ofCompound A which is substantially free of other solid forms comprisingCompound A including, e.g., Forms A, B, C, D, F, and/or an amorphoussolid form comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein. Certain embodiments herein provide Form E as a mixture of solidforms comprising Compound A, including, e.g., a mixture comprising oneor more of the following: Forms A, B, C, D, F, and an amorphous solidform comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein.

4.1.6. Form F of Compound A

Certain embodiments herein provide the Form F crystal form of CompoundA. In certain embodiments, Form F of Compound A can be obtained fromvarious solvents, including, but not limited to, solvent systemscomprising water. In certain embodiments, Form F can be obtained using aslurry recrystallization process.

In certain embodiments, Form F of Compound A may be characterized byX-ray powder diffraction analysis. A representative XRPD pattern of FormF of Compound A is provided in FIG. 16. In certain embodiments, Form Fof Compound A is characterized by XRPD peaks located at one, two, three,four, five, six, seven, eight, nine or ten of the following approximatepositions: 7.2, 9.1, 14.5, 15.7, 16.8, 18.3, 21.9, 22.7, 29.9 and 36.9degrees 2θ. In one embodiment, Form F of Compound A is characterized byXRPD peaks located at the following approximate positions: 14.5, 15.7,22.7 and 29.9 degrees 2θ. In certain embodiments, Form F of Compound Ais characterized by an XRPD pattern which matches the pattern exhibitedin FIG. 16. In certain embodiments, Form F of Compound A ischaracterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10peaks matching peaks in the representative Form F pattern providedherein.

In certain embodiments, Form F of Compound A may be characterized bythermal analysis. A representative DSC plot for Form F of Compound A isshown in FIG. 17. In certain embodiments, Form F is characterized by aDSC plot comprising an endothermic event with an onset temperature ofabout 267° C. In certain embodiments, a characteristic Form F DSC plotfurther comprises one additional event, such as, e.g., an exothermicevent with a peak temperature of about 170° C. In certain embodiments,Form F is solvated. In certain embodiments, Form F is hydrated.

Certain embodiments herein provide Form F of Compound A which issubstantially pure. Certain embodiments herein provide Form F ofCompound A which is substantially free of other solid forms comprisingCompound A including, e.g., Forms A, B, C, D, E, and/or an amorphoussolid form comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein. Certain embodiments herein provide Form F as a mixture of solidforms comprising Compound A, including, e.g., a mixture comprising oneor more of the following: Forms A, B, C, D, E, and an amorphous solidform comprising Compound A as provided herein, and Form A1 and anamorphous solid form comprising Compound A hydrochloride as providedherein.

4.1.7. Form A1 of Compound A Hydrochloride

Certain embodiments herein provide crystalline Form A1 of ahydrochloride salt of Compound A. In certain embodiments, Form A1 can beobtained from various solvents, including, but not limited to, solventsystems comprising acetone, acetonitrile, n-butanol, ethanol, ethylacetate, heptane, methanol, methylene chloride, methyl ethyl ketone,methyl t-butyl ether, 2-propanol, toluene, tetrahydrofuran, water, andmixtures thereof. In certain embodiments, Form A1 can be obtained usinga fast or slow cooling crystallization process. In certain embodiments,Form A1 can be obtained using an antisolvent addition crystallizationprocess.

Form A1 of Compound A hydrochloride is a stable crystalline form. Forexample, Form A1 found to be chemically stable upon storage at roomtemperature, exposed to air and light, for 6 weeks. Form A1 was alsofound to be chemically stable upon storage at 40° C. under vacuum. FormA1 was also found to be chemically stable upon storage at 40° C. under anitrogen atmosphere. Form A1 was also found to be chemically stable uponstorage at 40° C. and 75% relative humidity (RH). Form A1 was also foundto be chemically stable upon storage at 60° C. in a closed container.Based on this data, Form A1 of Compound A was determined to be suitablystable for large scale production (Example 5.4.3.2).

In certain embodiments, Form A1 may be characterized by X-ray powderdiffraction analysis. A representative XRPD pattern of Form A1 isprovided in FIG. 18. In certain embodiments, Form A1 is characterized byXRPD peaks located at one, two, three, four, five, six, seven, eight,nine or ten of the following approximate positions: 8.6, 11.3, 13.1,15.3, 17.3, 20.5, 22.7, 23.6, 26.3 and 31.4 degrees 2θ. In oneembodiment, Form A1 is characterized by XRPD peaks located at thefollowing approximate positions: 8.6, 13.1, 20.5 and 26.3 degrees 2θ. Incertain embodiments, Form A1 is characterized by an XRPD pattern whichmatches the pattern exhibited in FIG. 18. In certain embodiments, FormA1 is characterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 peaks matching peaks in the representative Form A1 patternprovided herein.

In certain embodiments, Form A1 of a hydrochloride salt of Compound Amay be characterized by thermal analysis. A representative DSC plot forForm A1 is shown in FIG. 19. In certain embodiments, Form A1 ischaracterized by a DSC plot comprising an endothermic event with anonset temperature of about 276° C. In certain embodiments, Form A1 has adecomposition temperature at about 276° C. A representative TGA plot forForm A1 of Compound A is shown in FIG. 20. In certain embodiments, FormA1 is characterized by a TGA plot comprising a mass loss of less thanabout 1%, less than about 0.5%, less than about 0.2%, less than about0.1%, less than about 0.05%, less than about 0.01%, e.g., about 0.0008%,of the total mass of the sample upon heating from about 25° C. to about150° C. In certain embodiments, Form A1 of Compound A does not containsubstantial amounts of either water or other solvent in the crystallattice. In certain embodiments, Form A1 is unsolvated. In certainembodiments, Form A1 is anhydrous.

In certain embodiments, Form A1 may be characterized by moisturesorption analysis. A representative moisture sorption isotherm plot isshown in FIG. 21. In certain embodiments, when the relative humidity(“RH”) is increased from about 0% to about 95% RH, Form A1 exhibits amass change of less than about 1%, less than about 0.5%, less than about0.2% (e.g., about 0.15%) of the starting mass of the sample. In certainembodiments, mass gained upon adsorption is lost when the RH isdecreased back to about 0% RH. Accordingly, in certain embodiments, FormA1 is substantially nonhygroscopic. In certain embodiments, the XRPDpattern of the Form A1 material is substantially unchanged following theadsorption/desorption analysis. In certain embodiments, Form A1 isstable with respect to humidity.

In certain embodiments, Form A1 of a hydrochloride salt of Compound Amay be characterized by its stability profile. In certain embodiments,Form A1 material is stable, e.g., its XRPD pattern remains substantiallyunchanged, upon exposure to elevated temperature, upon exposure toelevated humidity, upon exposure to one or more solvents, and/or uponcompression. In certain embodiments, for example, Form A1 is stablefollowing exposure to an environment of about 40° C. and about 75% RHenvironment for about four weeks. In certain embodiments, for example,Form A1 is stable following exposure to an environment of roomtemperature and about 95% RH environment for about four days. In certainembodiments, Form A1 is stable following exposure to one or more solventsystems comprising, e.g., acetone, acetonitrile, n-butanol, ethanol,ethyl acetate, heptane, methanol, methylene chloride, methyl ethylketone, methyl t-butyl ether, 2-propanol, toluene, and/ortetrahydrofuran at about 50° C. for at least about 24 hrs. In certainembodiments, Form A1 is stable upon compression at about 2,000-psipressure for about one minute.

In certain embodiments, Form A1 may be characterized by particleanalysis. In certain embodiments, a sample of Form A1 comprisesparticles having an acicular morphology.

Certain embodiments herein provide Form A1 Compound A which issubstantially pure. Certain embodiments herein provide Form A1 of ahydrochloride salt of Compound A, which is substantially free of othersolid forms comprising Compound A, including, e.g., an amorphous solidform comprising a hydrochloride salt of Compound A as provided herein,and Forms A, B, C, D, E, F, and/or an amorphous solid form comprisingCompound A as provided herein. Certain embodiments herein provide FormA1 as a mixture of solid forms comprising Compound A, including, e.g., amixture comprising one or more of the following: Forms A, B, C, D, E, F,and an amorphous solid form comprising Compound A as provided herein,and an amorphous solid form comprising Compound A hydrochloride asprovided herein.

Certain embodiments herein provide Form A1 of a hydrochloride salt ofCompound A, wherein the molar ratio of Compound A and hydrochloride inForm A1 is ranging from about 0.1 to about 10, from about 0.2 to about5, from about 0.5 to about 2, from about 0.6 to about 1.5, from about0.7 to about 1.3, from about 0.8 to about 1.2, from about 0.9 to about1.1, or from about 0.95 to about 1.05. In certain embodiments, the molarratio of Compound A and hydrochloride in Form A1 is about 0.5, about0.6, about 0.7, about 0.8, about 0.9, about 0.95, about 1, about 1.05,about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5.

4.2. Methods of Treatment

The disclosure encompasses methods of treating, preventing, and/ormanaging various diseases or disorders using a solid form of Compound Aor a stereoisomer thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, whichcomprise administering a therapeutically or prophylactically effectiveamount of one or more solid forms comprising Compound A, such as, e.g.,Form A, B, C, D, E, or an amorphous form of Compound A, or Form A1 or anamorphous form of Compound A hydrochloride as provided herein.

Without being limited by a particular theory, Compound A can controlangiogenesis or inhibit the production of certain cytokines including,but not limited to, TNF-α, IL-1β, IL-12, IL-18, GM-CSF, and/or IL-6.Without being limited by a particular theory, Compound A can stimulatethe production of certain other cytokines including IL-10, and also actas a costimulatory signal for T cell activation, resulting in increasedproduction of cytokines such as, but not limited to, IL-12 and/or IFN-γ.In addition, Compound A can enhance the effects of NK cells andantibody-mediated cellular cytotoxicity (ADCC). Further, Compound A maybe immunomodulatory and/or cytotoxic, and thus, may be useful aschemotherapeutic agents. Consequently, without being limited by aparticular theory, some or all of such characteristics possessed byCompound A may render them useful in treating, managing, and/orpreventing various diseases or disorders.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including, but notlimited to, Complex Regional Pain Syndrome (“CRPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases, pulmonarydisorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders, CNS injury, atherosclerosisand related disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNFα relateddisorders, and other various diseases and disorders.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Specific examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds provided herein can be used for treating,preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation.

In one embodiment, provided herein are methods of treating, preventingor managing various forms of leukemias such as chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia and acute myeloblastic leukemia, includingleukemias that are relapsed, refractory or resistant, as disclosed inU.S. publication no. 2006/0030594, published Feb. 9, 2006, which isincorporated in its entirety by reference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, provided herein are methods of treating,preventing or managing various types of lymphomas, includingNon-Hodgkin's lymphoma (NHL). The term “lymphoma” refers a heterogenousgroup of neoplasms arising in the reticuloendothelial and lymphaticsystems. “NHL” refers to malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract. Examples of NHL include, butare not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma (ILL),diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocyticlymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mentle zonelymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Examples of pain include, but are not limited to those described in U.S.patent publication no. 2005/0203142, published Sep. 15, 2005, which isincorporated herein by reference. Specific types of pain include, butare not limited to, nociceptive pain, neuropathic pain, mixed pain ofnociceptive and neuropathic pain, visceral pain, migraine, headache andpost-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS typeI, CRPS type II, reflex sympathetic dystrophy (RSD), reflexneurovascular dystrophy, reflex dystrophy, sympathetically maintainedpain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy,shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia,post herpetic neuralgia, cancer related pain, phantom limb pain,fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, centralpost-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain,luetic neuropathy, and other painful neuropathic conditions such asthose induced by drugs such as vincristine and velcade.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004, which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, keratoses and related symptoms, skindiseases or disorders characterized with overgrowths of the epidermis,acne, and wrinkles.

As used herein, the term “keratosis” refers to any lesion on theepidermis marked by the presence of circumscribed overgrowths of thehorny layer, including but not limited to actinic keratosis, seborrheickeratosis, keratoacanthoma, keratosis follicularis (Darier disease),inverted follicular keratosis, palmoplantar keratoderma (PPK, keratosispalmaris et plantaris), keratosis pilaris, and stucco keratosis. Theterm “actinic keratosis” also refers to senile keratosis, keratosissenilis, verruca senilis, plana senilis, solar keratosis, keratoderma orkeratoma. The term “seborrheic keratosis” also refers to seborrheicwart, senile wart, or basal cell papilloma. Keratosis is characterizedby one or more of the following symptoms: rough appearing, scaly,erythematous papules, plaques, spicules or nodules on exposed surfaces(e.g., face, hands, ears, neck, legs and thorax), excrescences ofkeratin referred to as cutaneous horns, hyperkeratosis, telangiectasias,elastosis, pigmented lentigines, acanthosis, parakeratosis,dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,cellular atypia, mitotic figures, abnormal cell-cell adhesion, denseinflammatory infiltrates and small prevalence of squamous cellcarcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratoses, sign of Leser-Trelat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A1, published Oct. 27,2005, which is incorporated herein by reference. Specific examplesinclude pulmonary hypertension and related disorders. Examples ofpulmonary hypertension and related disorders include, but are notlimited to: primary pulmonary hypertension (PPH); secondary pulmonaryhypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonaryhypertension; pulmonary arterial hypertension (PAH); pulmonary arteryhypertension; idiopathic pulmonary hypertension; thrombotic pulmonaryarteriopathy (TPA); plexogenic pulmonary arteriopathy; functionalclasses I to IV pulmonary hypertension; and pulmonary hypertensionassociated with, related to, or secondary to, left ventriculardysfunction, mitral valvular disease, constrictive pericarditis, aorticstenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonaryvenous drainage, pulmonary venoocclusive disease, collagen vasulardisease, congenital heart disease, HIV virus infection, drugs and toxinssuch as fenfluramines, congenital heart disease, pulmonary venoushypertension, chronic obstructive pulmonary disease, interstitial lungdisease, sleep-disordered breathing, alveolar hypoventilation disorder,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorder, chronic thromboemboli, connective tissue disease, lupusincluding systemic and cutaneous lupus, schistosomiasis, sarcoidosis orpulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, mesothelioma, asbestosis, malignantpleural effusion, benign exudative effusion, pleural plaques, pleuralcalcification, diffuse pleural thickening, rounded atelectasis, fibroticmasses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. publication no. 2006/0154880, published Jul. 13, 2006,which is incorporated herein by reference. Parasitic diseases includediseases and disorders caused by human intracellular parasites such as,but not limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L.donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana,L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C.parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S.haematobium, Trypanosoma ssp., Toxoplasma ssp., and O. volvulus. Otherdiseases and disorders caused by non-human intracellular parasites suchas, but not limited to, Babesia bovis, Babesia canis, Banesia Gibsoni,Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp., andTheileria ssp., are also encompassed. Specific examples include, but arenot limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis,toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. application Ser. No. 11/289,723, filed Nov. 30,2005. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-tenlangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344, published Jun. 30, 2005,which is incorporated herein by reference. Specific examples include,but are not limited to, include, but are not limited to, AmyotrophicLateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington'sDisease, Multiple Sclerosis other neuroimmunological disorders such asTourette Syndrome, delerium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. publication no. 2006/0122228,published Jun. 8, 2006, which is incorporated herein by reference.Specific examples include, but are not limited to, CNS injury/damage andrelated syndromes, include, but are not limited to, primary braininjury, secondary brain injury, traumatic brain injury, focal braininjury, diffuse axonal injury, head injury, concussion, post-concussionsyndrome, cerebral contusion and laceration, subdural hematoma,epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI,central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome,conus medullaris syndrome, cauda equina syndrome, neurogenic shock,spinal shock, altered level of consciousness, headache, nausea, emesis,memory loss, dizziness, diplopia, blurred vision, emotional lability,sleep disturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but not limited to, viral, genetic,allergic, and autoimmune diseases. Specific examples include, but notlimited to, HIV, hepatitis, adult respiratory distress syndrome, boneresorption diseases, chronic pulmonary inflammatory diseases,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft versus hostdisease, graft rejection, auto-immune disease, rheumatoid spondylitis,Crohn's disease, ulcerative colitis, inflammatory-bowel disease,multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy,radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated herein by reference.Specific examples include, but are not limited to, all forms ofconditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary by-pass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts.

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; Graft versus Host Reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, septis, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as septic shock,sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

In other embodiments, the use of Compound A in various immunologicalapplications, in particular, as vaccine adjuvants, particularlyanticancer vaccine adjuvants, as disclosed in U.S. ProvisionalApplication No. 60/712,823, filed Sep. 1, 2005, which is incorporatedherein in its entirety by reference, is also encompassed. Theseembodiments also relate to the use of Compound A in combination withvaccines to treat or prevent cancer or infectious diseases, and othervarious uses of immunomodulatory compounds such as reduction ordesensitization of allergic reactions.

Doses of a solid form of Compound A vary depending on factors such as:specific indication to be treated, prevented, or managed; age andcondition of a patient; and amount of second active agent used, if any.Generally, a solid form of Compound A provided herein may be used in anamount of from about 0.1 mg to about 500 mg per day, and can be adjustedin a conventional fashion (e.g., the same amount administered each dayof the treatment, prevention or management period), in cycles (e.g., oneweek on, one week off), or in an amount that increases or decreases overthe course of treatment, prevention, or management. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg.

A solid form of Compound A provided herein can be combined with otherpharmacologically active compounds (“second active agents”) in methodsand compositions provided herein. Certain combinations may worksynergistically in the treatment of particular types of diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. A solid form of Compound A provided herein can also work toalleviate adverse effects associated with certain second active agents,and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetlyase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransrerase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCL); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Omnitarg™)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin™)); VEGFR inhibitors (such as, forexample, flk-1 specific kinase inhibitors, SU5416 and ptk787/zk222584);P13K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents and antibiotics (e.g., clarithromycin).

Specific second active compounds that can be combined with a solid formof Compound A provided herein vary depending on the specific indicationto be treated, prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); 06-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another embodiment, examples of specific second agents according tothe indications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0122228, and 2005/0143344; and U.S. provisional application No.60/631,870.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2α, pentoxifylline, tin etiopurpurin,motexafin, lucentis, lutetium, 9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione, latanoprost(see U.S. Pat. No. 6,225,348), tetracycline and its derivatives,rifamycin and its derivatives, macrolides, metronidazole (U.S. Pat. Nos.6,218,369 and 6,015,803), genistein, genistin, 6′-O-Mal genistin,6′-O-Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O—Ac daidzin,glycitein, glycitin, 6′-O-Mal glycitin, biochanin A, formononetin (U.S.Pat. No. 6,001,368), triamcinolone acetomide, dexamethasone (U.S. Pat.No. 5,770,589), thalidomide, glutathione (U.S. Pat. No. 5,632,984),basic fibroblast growth factor (bFGF), transforming growth factor b(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen activatorfactor type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (EliLilly), Miravant, and RETISERT implant (Bausch & Lomb). All of thereferences cited herein are incorporated in their entireties byreference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hepertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin 12 (PGI2), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin,tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®),irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine,iloprost, betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agent,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenictrioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstiboglucuronate), interfereon gamma, itraconazole, a combination ofdead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: opioids; a dopamine agonist or antagonist, such as, but notlimited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine saliclate,physostigmine sulfate, physostigmine bromide, meostigmine bromide,neostigmine methylsulfate, ambenonim chloride, edrophonium chloride,tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betamethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprisesl-threo-methylphenidate, d-threo-methylphenidate,dl-threo-methylphenidate, l-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; hydroxy urea; HEMOXIN™ (NIPRISAN™; see U.S. Pat. No. 5,800,819);Gardos channel antagonists such as clotrimazole and triaryl methanederivatives; Deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

Administration of a solid form of Compound A provided herein and thesecond active agents to a patient can occur simultaneously orsequentially by the same or different routes of administration. Thesuitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. One ofadministration for a solid form of Compound A provided herein is oral.Routes of administration for the second active agents or ingredients areknown to those of ordinary skill in the art. See, e.g., Physicians' DeskReference (60^(th) ed., 2006).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a solid form of Compound A providedherein is administered daily in a single or divided doses in a four tosix week cycle with a rest period of about a week or two weeks. Cyclingtherapy further allows the frequency, number, and length of dosingcycles to be increased. Thus, another embodiment encompasses theadministration of a compound provided herein for more cycles than aretypical when it is administered alone. In yet another embodiment, acompound provided herein is administered for a greater number of cyclesthan would typically cause dose-limiting toxicity in a patient to whom asecond active ingredient is not also being administered.

In one embodiment, a solid form of Compound A provided herein isadministered daily and continuously for three or four weeks at a dose offrom about 0.1 mg to about 500 mg per day, followed by a rest of one ortwo weeks. In other embodiments, the dose can be from about 1 mg toabout 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg toabout 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg toabout 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about50 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20mg, followed by a rest.

In one embodiment, a solid form of Compound A provided herein and asecond active ingredient are administered orally, with administration ofthe compound provided herein occurring 30 to 60 minutes prior to thesecond active ingredient, during a cycle of four to six weeks. Inanother embodiment, the combination of a compound provided herein and asecond active ingredient is administered by intravenous infusion overabout 90 minutes every cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

4.3. Pharmaceutical Compositions

Pharmaceutical compositions and single unit dosage forms comprising oneor more solid forms comprising Compound A are provided herein. Alsoprovided herein are methods for preparing pharmaceutical compositionsand single unit dosage forms comprising one or more solid formscomprising Compound A. For example, in certain embodiments, individualdosage forms comprising a solid form provided herein or prepared usingsolid form provided herein may be suitable for oral, mucosal (includingrectal, nasal, or vaginal), parenteral (including subcutaneous,intramuscular, bolus injection, intraarterial, or intravenous),sublingual, transdermal, buccal, or topical administration.

In certain embodiments, pharmaceutical compositions and dosage formsprovided herein comprise one or more solid forms comprising Compound A.Certain embodiments herein provide pharmaceutical compositions anddosage forms comprising a solid form comprising Compound A, such as,e.g., Forms A, B, C, D, E, F or an amorphous solid form comprisingCompound A as provided herein, or Form A1 or an amorphous solid formcomprising Compound A hydrochloride as provided herein, wherein thesolid form comprising Compound A substantially pure. Certain embodimentsherein provide pharmaceutical compositions and dosage forms comprising asolid form comprising Compound A, such as, e.g., Forms A, B, C, D, E, F,or an amorphous solid form comprising Compound A as provided herein, orForm A1 or an amorphous solid form comprising Compound A hydrochlorideas provided herein, which is substantially free of other solid formscomprising Compound A including, e.g., Forms A, B, C, D, E, F, and/or anamorphous solid form comprising Compound A as provided herein, and FormA1 and/or an amorphous solid form comprising Compound A hydrochloride asprovided herein. Certain embodiments herein provide pharmaceuticalcompositions and dosage forms comprising a mixture of solid formscomprising Compound A, including, e.g., a mixture comprising one or moreof the following: Forms A, B, C, D, E, F, and an amorphous solid formcomprising Compound A as provided herein, and Form A1 and an amorphoussolid form comprising Compound A hydrochloride as provided herein.Pharmaceutical compositions and dosage forms provided herein typicallyalso comprise one or more pharmaceutically acceptable excipient, diluentor carrier.

A particular pharmaceutical composition encompassed by this embodimentcomprises one or more solid forms comprising Compound A and at least oneadditional therapeutic agent. Examples of additional therapeutic agentsinclude, but are not limited to: anti-cancer drugs and anti-inflammationtherapies including, but not limited to, those provided herein.

Single unit dosage forms of the disclosure are suitable for oral,mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal),parenteral (e.g., subcutaneous, intravenous, bolus injection,intramuscular, or intraarterial), or transdermal administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; ointments;cataplasms (poultices); pastes; powders; dressings; creams; plasters;solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels;liquid dosage forms suitable for oral or mucosal administration to apatient, including suspensions (e.g., aqueous or non-aqueous liquidsuspensions, oil-in-water emulsions, or a water-in-oil liquidemulsions), solutions, and elixirs; liquid dosage forms suitable forparenteral administration to a patient; and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the disclosure willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disorder may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed by this disclosure will varyfrom one another will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient may also depend on the specific active ingredientsin the dosage form.

Lactose-free compositions of the disclosure can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Preferred lactose-free dosage forms comprise an activeingredient, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

This disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising active ingredients, since watercan facilitate the degradation of some compounds. For example, theaddition of water (e.g., 5%) is widely accepted in the pharmaceuticalarts as a means of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the disclosurecan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The disclosure further encompasses pharmaceutical compositions anddosage forms that comprise one or more compounds that reduce the rate bywhich an active ingredient will decompose. Such compounds, which arereferred to herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms provided herein lie withinthe range of from about 1 mg to about 1,000 mg per day, given as asingle once-a-day dose in the morning but preferably as divided dosesthroughout the day. More specifically, the daily dose is administeredtwice daily in equally divided doses. Specifically, a daily dose rangemay be from about 5 mg to about 500 mg per day, more specifically,between about 10 mg and about 200 mg per day. In managing the patient,the therapy may be initiated at a lower dose, perhaps about 1 mg toabout 25 mg, and increased if necessary up to about 200 mg to about1,000 mg per day as either a single dose or divided doses, depending onthe patient's global response.

4.3.1. Oral Dosage Forms

Pharmaceutical compositions of the disclosure that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the disclosure are prepared by combiningthe active ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of thedisclosure include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the disclosure istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101™, AVICEL-PH-103™, AVICELRC-581™ AVICEL-PH-105™ (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Aspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581™. Suitable anhydrous orlow moisture excipients or additives include AVICEL-PH-103™ and Starch1500 LM™

Disintegrants are used in the compositions of the disclosure to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the disclosure. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the disclosure include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the disclosure include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200™, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL™ (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about one weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

4.3.2. Delayed Release Dosage Forms

Solid forms comprising Compound A as provided herein can be administeredby controlled release means or by delivery devices that are well knownto those of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of whichis incorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the disclosure. The disclosure thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.3.3. Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe disclosure are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the disclosure.

4.3.4. Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the disclosureinclude, but are not limited to, ophthalmic solutions, sprays, aerosols,creams, lotions, ointments, gels, solutions, emulsions, suspensions, orother forms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this disclosure are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the disclosure. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80™(polysorbate 80) and Span 60™ (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different solid forms comprising the activeingredients can be used to further adjust the properties of theresulting composition.

4.3.5. Kits

This disclosure encompasses kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a patient.

A typical kit of the disclosure comprises a unit dosage form of compoundA, or a pharmaceutically acceptable solid form or prodrug thereof, and aunit dosage form of a second active ingredient. Examples of secondactive ingredients include, but are not limited to, those listed herein.

Kits of the disclosure can further comprise devices that are used toadminister the active ingredient(s). Examples of such devices include,but are not limited to, syringes, drip bags, patches, and inhalers.

Kits of the disclosure can further comprise pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:Water for Injection USP; aqueous vehicles such as, but not limited to,Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles such as, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehiclessuch as, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5. EXAMPLES 5.1. Example 1 Assays

5.1.1. TNFα Inhibition Assay in PMBC

Peripheral blood mononuclear cells (PBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPMI 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mLpenicillin, and 100 μg/mL streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat. no. L-1887, St.Louis, Mo., USA) at 1 ng/mL final in the absence or presence ofcompounds. Compounds provided herein are dissolved in DMSO (Sigma) andfurther dilutions are done in culture medium immediately before use. Thefinal DMSO concentration in all assays can be about 0.25%. Compounds areadded to cells 1 hour before LPS stimulation. Cells are then incubatedfor 18-20 hours at 37° C. in 5% CO₂, and supernatants are thencollected, diluted with culture medium and assayed for TNFα levels byELISA (Endogen, Boston, Mass., USA). IC₅₀s are calculated usingnon-linear regression, sigmoidal dose-response, constraining the top to100% and bottom to 0%, allowing variable slope (GraphPad Prism v3.02).In two experiments, Compound A demonstrated an IC₅₀ of 10 and 85 nM.

5.1.2. IL-2 and MIP-3α Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mLcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/mL penicillin, and 100 μg/mLstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×10⁸ non-adherent PBMC: 0.3 mL Sheep anti-mouse IgG beads, 15 μLanti-CD16, 15 μL anti-CD33, 15 μL anti-CD56, 0.23 mL anti-CD19 beads,0.23 mL anti-HLA class II beads, and 56 μL anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3⁺ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/mL in PBS, 100 μL per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μL/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds provided herein is diluted 1:50 in complete for the first 20×dilution of 200 μM in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3α by ELISA (R&DSystems). IL-2 and MIP-3α levels are normalized to the amount producedin the presence of an amount of a compound provided herein, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

5.1.3. Cell Proliferation Assay

Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig,Germany). The cell line KG-1 is obtained from the American Type CultureCollection (Manassas, Va., USA). Cell proliferation as indicated by³H-thymidine incorporation is measured in all cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μL/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

5.1.4. Immunoprecipitation and Immunoblot

Namalwa cells are treated with DMSO or an amount of a compound providedherein for 1 hour, then stimulated with 10 U/mL of Epo (R&D Systems) for30 minutes. Cell lysates are prepared and either immunoprecipitated withEpo receptor Ab or separated immediately by SDS-PAGE. Immunoblots areprobed with Akt, phospo-Akt (Ser473 or Thr308), phospho-Gab1 (Y627),Gab1, IRS2, actin and IRF-1 Abs and analyzed on a Storm 860 Imager usingImageQuant software (Molecular Dynamics).

5.1.5. Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound provided hereinovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

5.1.6. Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound provided hereinat various time points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

5.1.7. Luciferase Assay

Namalwa cells are transfected with 4 μg of AP1-luciferase (Stratagene)per 1×10⁶ cells and 3 μL Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound provided herein.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

5.2. Example 2 Preparation of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione(Compound A)

Step 1: To a solution of potassium hydroxide (16.1 g, 286 mmol) in water(500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at0° C. The suspension was stirred at 0° C. for 3 hrs, and then heated to30° C. for 3 hrs. To the solution, was added HCl (100 mL, 6N). Theresulting suspension was cooled to 0° C. for 1 hr. The suspension wasfiltered and washed with cold water (2×10 mL) to give 3-nitro-phthalamicacid as a white solid (24.6 g, 90% yield): ¹H NMR (DMSO-d₆) δ 7.69 (brs,1H, NHH), 7.74 (t, J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13(dd, J=1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); ¹³C NMR(DMSO-d₆) δ 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90,167.31.

Step 2: To a mixture of 3-nitro-phthalamic acid (24.6 g, 117 mmol) andpotassium hydroxide (6.56 g, 117 mmol) in water (118 mL), was added amixture of bromine (6 mL), potassium hydroxide (13.2 g, 234 mmol) inwater (240 mL) at 0° C., followed by addition of a solution of potassiumhydroxide (19.8 g, 351 mmol) in water (350 mL). After 5 minutes at 0°C., the mixture was heated in a 100° C. oil bath for 1 hr. The reactionsolution was cooled to room temperature, and then, in an ice-water bathfor 30 minutes. To the mixture, a solution of HCl (240 mL, 2N) was addeddropwise at 0° C., and the resulting mixture was kept for 1 hr. Thesuspension was filtered and washed with water (5 mL) to give2-amino-6-nitro-benzoic acid as yellow solid (15.6 g, 73% yield): HPLC:Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, CH₃CN/0.1%H₃PO₄, 5% grad to 95% over 5 min, 5.83 min (85%); ¹H NMR (DMSO-d₆) δ6.90 (dd, J=1, 8 Hz, 1H, Ar), 7.01 (dd, J=1, 9 Hz, 1H, Ar), 7.31 (t, J=8Hz, 1H, Ar), 8.5-9.5 (brs, 3H, OH, NH₂); ¹³C NMR (DMSO-d₆) δ 105.58,110.14, 120.07, 131.74, 149.80, 151.36, 166.30; LCMS: MH=183.

Step 3: A mixture of 2-amino-6-nitro-benzoic acid (1.5 g, 8.2 mmol) inacetic anhydride (15 mL) was heated at 200° C. for 30 minutes in amicrowave oven. The mixture was filtered and washed with ethyl acetate(20 mL). The filtrate was concentrated in vacuo. The solid was stirredin ether (20 mL) for 2 hrs. The suspension was filtered and washed withether (20 mL) to give 2-methyl-5-nitro-benzo[d][1,3]oxazin-4-one as alight brown solid (1.4 g, 85% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, CH₃CN/0.1% H₃PO₄, 5% grad 95% in 5 min,5.36 min (92%); ¹H NMR (DMSO-d₆) δ 2.42 (s, 3H, CH₃), 7.79 (dd, J=1, 8Hz, 1H, Ar), 7.93 (dd, J=1, 8 Hz, 1H, Ar), 8.06 (t, J=8 Hz, 1H, Ar); ¹³CNMR (DMSO-d₆) δ 20.87, 107.79, 121.54, 128.87, 137.19, 147.12, 148.46,155.18, 161.78; LCMS: MH=207.

Step 4: Two vials each with a suspension of5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one (0.60 g, 2.91 mmol) and3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol) inpyridine (15 mL) were heated at 170° C. for 10 minutes in a microwaveoven. The suspension was filtered and washed with pyridine (5 mL). Thefiltrate was concentrated in vacuo. The resulting mixture was stirred inHCl (30 mL, 1N), ethyl acetate (15 mL) and ether (15 mL) for 2 hrs. Thesuspension was filtered and washed with water (30 mL) and ethyl acetate(30 mL) to give a dark brown solid, which was stirred with methanol (50mL) at room temperature overnight. The suspension was filtered andwashed with methanol to give3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as ablack solid (490 mg, 27% yield). The solid was used in the next stepwithout further purification.

Step 5: A mixture of3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (250mg) and Pd(OH)₂ on carbon (110 mg) in DMF (40 mL) was shaken underhydrogen (50 psi) for 12 hrs. The suspension was filtered through a padof Celite and washed with DMF (10 mL). The filtrate was concentrated invacuo and the resulting oil was purified by flash column chromatography(silica gel, methanol/methylene chloride) to give3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (156 mg, 69% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, 3.52 min (99.9%);mp: 293-295° C.; ¹H NMR (DMSO-d₆) δ 2.10-2.17 (m, 1H, CHH), 2.53 (s, 3H,CH₃), 2.59-2.69 (m, 2H, CH₂), 2.76-2.89 (m, 1H, CHH), 5.14 (dd, J=6, 11Hz, 1H, NCH), 6.56 (d, J=8 Hz, 1H, Ar), 6.59 (d, J=8 Hz, 1H, Ar), 7.02(s, 2H, NH₂), 7.36 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.98, 23.14, 30.52, 55.92, 104.15, 110.48, 111.37, 134.92,148.17, 150.55, 153.62, 162.59, 169.65, 172.57; LCMS: MH=287; Anal.Calcd. for C₁₄H₁₄N₄O₃+0.3 H₂O: C, 57.65; H, 5.05; N, 19.21. Found: C,57.50; H, 4.73; N, 19.00.

5.3. Example 3 Preparation of Compound A Hydrochloride

In a stirred glass flask, approximately 19 g of Compound A (freebase)was suspended in approximately 200 mL acetonitrile and 200 mL water.Approximately 5 mL 12 N hydrochloric acid was added, and the suspensionwas dissolved by heating above 55° C. The solution was cooled to approx45° C. and seed crystals of Compound A Form A1 (e.g. Hydrochloride) wereadded to the flask. Then 6 N hydrochloric acid was added dropwisecausing further crystallization. The slurry was slowly cooled. Theslurry was then filtered and the cake was washed with acetonitrile. Theproduct was then dried in a vacuum oven. The resulting dry product wasconsistent with Compound A Form A1.

5.4. Example 4 Solid Form Screening Studies

5.4.1. Experimental Methodology

The methods described herein are illustrated with Compound Ahydrochloride. These methods can be used directly or with somemodification for other solids forms of Compound A as described herein.

Solubility: A weighed sample of Compound A hydrochloride (about 50 mg)was treated with a known volume of a test solvent. The solvents usedwere either reagent or HPLC grade. The resulting mixture was agitatedfor at least 24 hours at about 25° C. If all of the solids appeared tobe dissolved by visual inspection, the estimated solubilities werecalculated based on the total volume of solvent used to give a completesolution. The actual solubilities may be greater than those calculateddue to the use of large amount of solvent or to a slow rate ofdissolution. If solids were present, the solubility was measuredgravimetrically. A known volume of filtrate was evaporated to drynessand the weight of the residue was measured.

Equilibration/Slurry and Evaporation: Equilibration and evaporationexperiments were carried out by adding an excess of Compound Ahydrochloride to about 2 mL of a test solvent. The resulting mixture wasagitated for at least 24 hrs at about 25° C. or about 50° C. Uponreaching equilibrium, the saturated solution was removed and allowed toevaporate slowly in an open vial under nitrogen at about 25° C. andabout 50° C., respectively. The solids resulting from the equilibrationwere filtered and dried in the air.

Cooling Recrystallization: The selected solvents (THF/water, MeCN/water,MeOH/0.1N HCl, and EtOH/0.1N HCl) were saturated with Compound Ahydrochloride at about 50-70° C. Once the solids were completelydissolved, the solution was rapidly cooled by placing into arefrigerator (about 0-5° C.). Solids were isolated after 1 to 3 days.

Solvent/Anti-Solvent Recrystallization: The selected solvent(MeCN/water) was saturated with Compound A hydrochloride at roomtemperature. Once the solids were completely dissolved, an anti-solvent(acetone or IPA) was added into the solution. The mixture was stirred atroom temperature overnight. If no precipitation occurred, the vial wasfurther cooled by placing into a refrigerator (about 0-5° C.). Thesolids resulting from the recrystallization were filtered and air-dried.

Grinding Studies: Grinding experiments were performed using a Wig-L-Bugshaker. About 50 mg of Compound A hydrochloride was added to apolystyrene tube (1″×½″) with a Plexi bead (⅜″). The vial was capped andplaced on the shaker for about 50 s. For wet grinding, drops of waterwere added to the vial and a wet paste was formed prior to placing onthe shaker.

Humidity Studies: About 30 mg of Compound A hydrochloride was placed inamber glass vials in duplicate. The vials were placed in 40° C./75% RHhumidity chamber with one vial capped and one vial open. The solids weretested by XRPD after four weeks. An additional humidity stressexperiment was performed by placing about 10 mg of Compound Ahydrochloride in a DVS instrument at 95% RH and room temperature forfour days.

5.4.2. Characterization Methodology

X-ray Powder Diffraction (XRPD): XRPD analysis was conducted on a ThermoARL X'TRA™ X-ray powder diffractometer using Cu Kα radiation at 1.54 Å.The instrument was equipped with a fine focus X-ray tube. The voltageand amperage of X-ray generator were set at 45 kV and 40 mA,respectively. The divergence slices were set at 4 mm and 2 mm and themeasuring slices were set at 0.5 mm and 0.2 mm. Diffracted radiation wasdetected by a peltier-cooled Si(Li) solid-state detector. A theta-twotheta continuous scan at 2.40°/min (0.5 sec/0.02° step) from 1.5°2θ to40°2θ was used. A sintered alumina standard was used to check the peakposition. In general, positions of XRPD peaks are expected toindividually vary on a measurement-by-measurement basis by about+0.2°2θ. In general, as understood in the art, two XRPD patterns matchone another if the characteristic peaks of the first pattern are locatedat approximately the same positions as the characteristic peaks of thesecond pattern. As understood in the art, determining whether two XRPDpatterns match or whether individual peaks in two XRPD patterns matchmay require consideration of individual variables and parameters suchas, but not limited to, preferred orientation, phase impurities, degreeof crystallinity, particle size, variation in diffractometer instrumentsetup, variation in XRPD data collection parameters, and/or variation inXRPD data processing, among others. The determination of whether twopatterns match may be performed by eye and/or by computer analysis.

Differential Scanning Calorimetry (DSC): DSC analyses were performed ona TA Instruments Q2000™ differential scanning calorimeter. Indium wasused as a calibration standard. About 2-5 mg of a sample was placed into a DSC pan. The sample was heated under nitrogen at a rate of 10°C./min from about 25° C. up to a final temperature of 300° C. Meltingpoints were reported as the extrapolated onset temperatures.

Thermal Gravimetric Analyses (TGA): TGA analyses were performed on a TAInstruments Q5000™ thermogravimetric analyzer. Calcium oxalate was usedfor calibration. About 5-20 mg of an accurately weighted sample wasplaced on a pan, and loaded into the TGA furnace. The sample was heatedunder nitrogen at a rate of about 10° C./min up to a final temperatureof about 300° C.

Optical Microscopy: Morphology analysis of a sample was carried out onan Olympus microscope. Small amounts of a sample were dispersed inmineral oil on a glass slide with cover slips and viewed with 20×magnification.

Dynamic Vapor Sorption (DVS): Hygroscopicity was determined on a SurfaceMeasurement Systems DVS. Typically, a sample of about 2-10 mg was loadedinto the DVS instrument sample pan. The sample was analyzed on a DVSautomated sorption analyzer at room temperature. The relative humiditywas increased from 0 to 95% RH at 10% RH step, then at 95% RH. Therelative humidity was then decreased in a similar manner to accomplish afull adsorption/desorption cycle.

Solubility by HPLC: Solubility of Form A in selected aqueous and organicsolvents was determined by mixing solid with solvents at roomtemperature. The samples were filtered after 24 hr of agitation andquantified by an HPLC method, except for DMSO, for which the solubilitywas measured after 1 hr of agitation.

5.4.3. Solid Form Screening Study Results

Solid forms comprising Compound A which were prepared during the solidform screening studies included Form A, B, C, D, E, F, and A1, andamorphous forms. Representative XRPD patterns, DSC plots, TGA plots andDVS plots for Form A, B, C, D, E, F, and I are provided herein as FIGS.1 to 21.

5.4.3.1. Solid Forms of Compound A

Interconversions between various solid forms of Compound A aresummarized in FIG. 23. The interconversion conditions as depicted inFIG. 23 are:

-   -   1. Slurry in MeOH at RT, or in acetone, MeCN, or MeOH at 50° C.    -   2. Slurry in EtOAC, EtOH, IPA, MEK, n-BuOH or THF at 50° C.    -   3. Dried in vacuum oven at ˜70° C.    -   4. Slurry in MeCN or IPA at RT    -   5. Slurry in EtOH at RT    -   6. Slurry in water at RT    -   7. Slurry in organic solvents at RT or elevated temperature    -   8. Exposure to moisture at RT    -   9. Slurry in water at RT    -   10. Slurry in organic solvents at elevated temperature    -   11. Slurry in water at RT    -   12. Exposure to moisture in DVS        The physical properties of Forms A, B, C, D, E, and F are        summarized in Table 2.

TABLE 2 Characteristics of Solid Forms of Compound A TGA Moisture LossSorption at DSC Peaks (wt 95% RH (wt Form Morphology (° C.) %) %)Comment A Crystalline 145.3 (broad) 5.87 3.19 Mono- Irregular 161.2(exo) hydrate plate 282.1 (onset) B Crystalline 279.0 (onset) 0.00 0.11Anhydrate Irregular shape C Crystalline 280.7 (onset) 0.07 0.17Anhydrate Irregular shape D Semi- 114.4 (broad) 3.04 4.11 Unstablecrystalline 283.3 (onset) dehy- Irregular shape drated form ECrystalline 147.0 (broad) 5.98 0.26 Hydrate/ Large irregular 279.4(onset) solvate plate F Crystalline 170.4 (exo) 266.5 (onset)

In a stirred glass flask, 3.5 g Compound A freebase was dissolved inapprox 14 mL DMSO and approx 0.7 mL water at room temperature. Approx 2mL water was added and crystals of Compound A Form A began to form.Additional water was added dropwise and the batch further crystallized.The batch was then filtered. The cake was washed with a 1:1 (v:v)DMSO:water solution and neat water. The wet cake was dried in a vacuumoven. The final dry product was consistent with Compound A Form A.

Alternatively, Compound A Form A can be obtained by seeding. In astirred glass flask, 3.5 g Compound A freebase was dissolved in approx14 mL DMSO and approx 0.7 mL water at room temperature. Approx 1.3 mLwater was added, and seeds of Compound A Form A were added, and thebatch began to crystallize. Additional water was added dropwise, and thebatch further crystallized. The batch was then filtered. The cake wasthen washed with 1:1 (v:v) DMSO:water solution and neat water. The wetcake was dried in a vacuum oven. The final dry product was consistentwith Compound A Form A.

Form B of Compound A was prepared from Form A via slurryrecrystallization in methanol, acetone or acetonitrile. The slurryexperiments were carried out by adding an excess of Compound A to 2 mLof methanol, acetone or acetonitrile. The resulting mixture was agitatedfor at least 24 hours at about 50° C. Upon reaching equilibrium, thesolid was filtered and air dried.

Form C of Compound A was prepared from Form A via slurryrecrystallization in EtOAc, EtOH, IPA, MEK, n-BuOH, or THF at about 50°C. The slurry experiments were carried out by adding an excess ofCompound A to 2 mL of EtOAc, EtOH, IPA, MEK, n-BuOH, or THF. Theresulting mixture was agitated for at least 24 hours at about 50° C.Upon reaching equilibrium, the solid was filtered and air dried.

Form D of Compound A was prepared from Form A via drying Form A invacuum oven at about 80-90° C.

Form E of Compound A was prepared from Form A via slurryrecrystallization in acetonitrile, ethanol or isopropanol at roomtemperature. The slurry experiments were carried out by adding an excessof Compound A to 2 mL of acetonitrile, ethanol or isopropanol. Theresulting mixture was agitated for at least 24 hours at roomtemperature. Upon reaching equilibrium, the solid was filtered and airdried.

Form F of Compound A was prepared from Form B via slurryrecrystallization in water at room temperature. The slurry experimentwas carried out by adding an excess of Compound A to 2 mL of water. Theresulting mixture was agitated for at least 16 hours at roomtemperature. The solid was then filtered and air dried.

5.4.3.2. Solid Form A1 of Compound A HCl

Form A1, a hydrochloride salt of Compound A was prepared by thefollowing process. In a stirred glass flask, 2 g Compound Ahydrochloride was mixed in a solvent mixture of approximately 20 mLacetonitrile and 20 mL water and dissolved by heating to >55° C. Thesolution was cooled to 45° C. and approx 3.3 mL 6 N hydrochloric acidwas added, causing crystallization. The slurry was then slowly cooledand filtered. The cake was washed with acetonitrile and then dried in avacuum oven. The resulting dry product was consistent with Compound AForm A1.

Large Scale Process.

Form A1 was prepared on a large scale by combining 100 g of Compound Ahydrochloride, 960 mL acetonitrile and 960 mL deionized water in areactor. The mixture was heated with agitation to 60 to 70° C. andtransferred to a second reactor by an inline filter (0.45 μm). The firstreactor is rinsed with 100 mL of acetonitrile:water (1:1), which wastransferred to the second reactor by the inline filter. The temperaturein the second reactor was maintained at 65° C. during transfer. Thesecond reactor was then cooled to 45° C. and seeded with 3 g Form A1crystals. The batch began to crystallize and was aged at 45° C. for 30minutes. To the resulting slurry was added 171 mL 6 N HCl by an inlinefilter over 1 hour, maintaining batch temperature at about 45° C. Thebatch was aged at 45° C. for 1.5 hours and cooled to 0° C. in a linearramp over 4 hours. The batch was then aged at 0° C. for 1 hour. Thesupernatant was sampled for UPLC concentration. The concentration ofForm A1 in the supernatant was 5 mg/mL. The slurry was filtered througha fritted glass filter with vacuum. The resulting cake was displacementwashed with 2×300 mL acetonitrile washes. The cake was dried in a vacuumoven at 40° C. until acetonitrile is <400 ppm. The dry cake of Form A1was a clean white/off-white powder.

It was discovered that acetonitrile:water was the only solvent systemwhich afforded acceptable properties for scaleup, e.g., solubilitygreater than about 50 g/mL product. Excess HCl was added to preventformation of the free base of Compound A. In some cases it was foundthat the absence of HCl in the process resulted in free base formation.Excess HCl was also thought to improve Form A1 yield duringcrystallization.

The physical properties from the HCl salt are consistent from batch tobatch. TGA shows little residual solvent (also, by NMR residualacetonitrile can be reduced to <400 ppm). DSC shows a single event at˜280° C., which is considered to be decomposition (similar to thedecomposition point of the freebase). Microscopy showed long rodmorphology.

Solubility Studies.

The approximate solubility of Form A1 of Compound A hydrochloride invarious solvents at about 25° C. was determined. Form A1 was found to bemost soluble (>25 mg/mL) in MeCN/water (1:1) and THF/water (1:1). FormA1 was found to have moderate solubility (3-10 mg/mL) in EtOH/water(1:1), MeOH, CH₂Cl₂, THF, and water. Form A1 was found to have lowsolubility (<3 mg/mL) in other organic solvents tested. The solubilityof Form A1 in selected solvents was also tested by HPLC and results areshown in Table 3.

TABLE 3 Solubility Solvent Solubility (mg/mL) Water 1.71 0.9% NaCl 1.900.1N HCl 5.34 Acetate buffer (pH 4.0) 0.31 Phosphate buffer (pH 6.8)0.03 Acetonitrile (AcCN) 0.02 Acetone 2.55 Methanol (MeOH) 0.27Isopropanol (iPrOH) 0.02 Ethyl acetate (EtOAc) <0.001 Tetrahydrofuran(THF) <0.005 Heptane <0.001 Toluene <0.005 Dimethyl Sulfoxide (DMSO)21.88

Slurry experiments were performed at room temperature and 50° C. usingForm A1 of Compound A hydrochloride as starting material. The resultsare summarized in Tables 4 and 5. All of the solids isolated from pureorganic solvents after 24 hrs of slurry were confirmed to be Form A1 byXRPD. The solid isolated from THF/water at 50° C. slurry was alsoconfirmed to be Form A1. The solids isolated from other aqueous/organicor aqueous slurries were shown be to mixtures of Form A1 and Compound Afree base, suggesting partial dissociation of the HCl salt.

TABLE 4 Equilibration Experiments at Room Temperature. Solvent XRPDResult Acetone Form A1 Acetonitrile Form A1 n-Butanol Form A1 EthanolForm A1 Ethyl acetate Form A1 Heptane Form A1 Methanol Form A1 Methylenechloride Form A1 Methyl ethyl ketone Form A1 Methyl t-butyl ether FormA1 2-Propanol Form A1 Toluene Form A1 Tetrahydrofuran Form A1 Water FormA + Form A1 Ethanol/Water (1:1) Form A + Form A1 Acetonitrile/Water(1:1) Form A + Form A1 Tetrahydrofuran/Water (1:1) Form A + Form A1

TABLE 5 Equilibration Experiments at 50° C. Solvent XRPD Result AcetoneForm A1 Acetonitrile Form A1 n-Butanol Form A1 Ethanol Form A1 Ethylacetate Form A1 Heptane Form A1 Methanol Form A1 Methyl ethyl ketoneForm A1 2-Propanol Form A1 Toluene Form A1 Tetrahydrofuran Form A1 WaterForm A + Form A1 Ethanol/Water (1:1) Form A + Form A1 Acetonitrile/Water(1:1) Form A + Form A1 Tetrahydrofuran/Water (1:1) Form A1

Evaporation experiments were performed. The results are summarized inTables 6 and 7. For room temperature evaporations, solids obtained fromwater, EtOH/water, and MeCN/water were confirmed to be Form A1. Partialor complete salt dissociation were observed in MeOH, THF, and THF/water.For 50° C. evaporations, solids obtained from MeOH, water, EtOH/water,and MeCN/water were confirmed to be Form A1. Solid from THF/water wasshown to be amorphous.

TABLE 6 Evaporation Experiments at Room Temperature Solvent XRPD ResultAcetone N/A Acetonitrile N/A n-Butanol N/A Ethanol N/A Ethyl acetate N/AHeptane N/A Methanol Form A + Form A1 Methyl ethyl ketone N/A 2-PropanolN/A Toluene N/A Tetrahydrofuran N/A Water Form A1 Ethanol/Water (1:1)Form A1 Acetonitrile/Water (1:1) Form A1 Tetrahydrofuran/Water (1:1)Form A + Form A1

TABLE 7 Evaporation Experiments at 50° C. Solvent XRPD Result AcetoneN/A Acetonitrile N/A n-Butanol N/A Ethanol N/A Ethyl acetate N/A HeptaneN/A Methanol Form A1 Methyl ethyl ketone N/A 2-Propanol N/A Toluene N/ATetrahydrofuran N/A Water Form A1 Ethanol/Water (1:1) Form A1Acetonitrile/Water (1:1) Form A1 Tetrahydrofuran/Water (1:1) Amorphous

Recrystallization experiments were performed in several organic/aqueousmixtures. The results are summarized in Table 8. Solids from MeCN/water,MeOH/0.1N HCl, or EtOH/0.1N HCl were confirmed to be Form A1. Completesalt dissociation was observed in THF/water.

Anti-solvent crystallization was also performed with MeCN/water as theprimary solvent system, and with acetone or IPA as antisolvent. Form A1was obtained when acetone was used as antisolvent, and partial saltdissociation was observed when IPA was used as antisolvent.

TABLE 8 Recrystallization without and with Antisolvents Ratio (Solvent/Solvent Antisolvent Antisolvent) XRPD Result THF/H₂O NA NA Form AMeCN/H₂O NA NA Form A1 + Form A MeOH/0.1N HCl NA NA Form A1 EtOH/0.1NHCl NA NA Form A1 MeCN/H₂O Acetone 1:5 Form A1 MeCN/H₂O IPA 1:5 FormAl + Form A

Grinding experiments were performed with and without addition of water,as a further attempt to generate polymorphs. Form A1 was found unchangedupon grinding. The results are summarized in Table 9.

TABLE 9 Grinding Experiments Starting Form Test Conditions XRPD ResultForm A Dry grinding Form A1 Form A Wet grinding (paste) Form A1

Characterization of Form A1

Form A1 had a crystalline XRPD pattern as shown in FIG. 18 and acicularcrystal habit. TGA and DSC thermograms of Form A1 are shown in FIGS. 19and 20, respectively. Negligible weight loss was observed prior todecomposition, the onset temperature of which was about 276° C. asdetermined by DSC.

The moisture sorption/desorption behavior of Form A1 was determined byDVS and the results are summarized in FIG. 21. Form A1 exhibited a 0.15%mass change relative to the dry mass when the relative humidity wasincreased from 0 to 95%, indicating that the material isnon-hygroscopic. After undergoing the full adsorption/desorption cycle,the XRPD diffractogram of the sample showed that the material wasunchanged from the initial Form A1.

Stability of Form A1 was determined by exposing the sample to a 40°C./75% RH environment for four weeks or 95% RH at room temperature forfour days. Solid form of the exposed material was not changed comparedto the initial unexposed sample (Table 10). Form A1 was also found to bestable upon application of 2000-psi pressure for about 1 minute.

TABLE 10 Grinding Experiments Starting Form Test Conditions XRPD ResultForm A1 40° C./75% RH for Form A1 4 weeks, open vial Form A1 40° C./75%RH for Form A1 4 weeks, closed vial Form A1 95% RH for 4 days Form A1

Based on these characterization studies, Form A1 was found to be astable anhydrous and non-hygroscopic crystalline material.

While the disclosure has been described with respect to the particularembodiments, it will be apparent to those skilled in the art thatvarious changes and modifications may be made without departing from thespirit and scope of the disclosure as defined in the claims. Suchmodifications are also intended to fall within the scope of the appendedclaims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art to this disclosure. Thefull scope of the disclosure is better understood with reference to theappended claims.

What is claimed is:
 1. A method of treating or managing a disease ordisorder comprising administering to a patient having the disease ordisorder a solid form comprising a hydrochloride salt of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione:

having an X-ray powder diffraction pattern comprising peaks atapproximately 8.6° 2θ, 13.1° 2θ, 20.5° 2θ and 26.3° 2θ, wherein thedisease or disorder is leukemia, lymphoma, myeloma, myelodysplasticsyndrome, or myeloproliferative disease.
 2. The method of claim 1,wherein the disease or disorder is leukemia or lymphoma.
 3. The methodof claim 2, wherein the lymphoma is Hodgkin's lymphoma.
 4. The method ofclaim 2, wherein the lymphoma is Non-Hodgkin's lymphoma.
 5. The methodof claim 4, wherein the Non-Hodgkin's lymphoma is cutaneous T-celllymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma,Waldenstrom's macrogliobineima, mantle cell lymphoma, or follicularlymphoma.
 6. The method of claim 2, wherein the leukemia is chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia, or acute myeloblastic leukemia. 7.The method of claim 1, wherein the disease or disorder is multiplemyeloma, smoldering myeloma, or indolent myeloma.
 8. The method of claim7, wherein the disease or disorder is multiple myeloma.
 9. The method ofclaim 1, wherein the disease or disorder is myelodysplastic syndrome ormyeloproliferative disease.
 10. The method of claim 5, wherein theNon-Hodgkin's lymphoma is diffuse large B-cell lymphoma.